The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Diabetic Retinopathy
To the Editor: In their review article on diabetic retinopathy (March 29 issue),1 Antonetti et al. describe the retinal dysfunction associated with diabetes as a change in the retinal neurovascular unit, alluding to energy homeostasis, but do not refer to the article by Arden.2 In this article, Arden points out that the 120 million rods have the highest metabolic rate of any cell, requiring a great deal of energy and oxygen, especially in the dark.3 Since the rods are avascular, the partial pressure of oxygen among the mitochondria is essentially zero. Thus, in dark adaptation, the retina uses so much oxygen that it is nearly pathologically anoxic and at risk if the oxygen supply is reduced. Arden reports on patients with absent rod function (i.e., with retinitis pigmentosa) and coexisting diabetes. In contrast to an expected rate of diabetic retinopathy of 40% in such patients, the condition did not develop in any of these cases. This finding may provide the link to obstructive sleep apnea. The hypoxic load that obstructive sleep apnea delivers has been linked to the development of diabetic retinopathy, and intervention with continuous positive airway pressure has been shown to be beneficial.4,5 Panagis Drakatos, M.D. Christopher Kosky, M.B. Adrian J. Williams, M.B.
Guys and St. Thomas NHS Foundation Trust London, United Kingdom ajwsleep@gmail.com No potential conflict of interest relevant to this letter was reported.
1. Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. 2. Arden GB. The absence of diabetic retinopathy in patients

To the Editor: Antonetti et al. describe emerging therapeutic targets beyond vascular endothelial growth factor (VEGF) signaling in patients with diabetic retinopathy, such as the platelet-derived growth factor (PDGF) pathway. Although the authors emphasize the salutary role of PDGF as a prosurvival cytokine to maintain pericyte viability and normal vascularization in transgenic mouse models of diabetic retinopathy, studies in humans have suggested the opposite effect. In fact, several studies have shown elevated PDGF concentrations in vitreous samples from patients with diabetic retinopathy.1,2 Like VEGF, PDGF is a proangiogenic growth factor that may promote aberrant neovascularization in diabetic retinopathy.3 Furthermore, PDGF may stimulate the formation and traction of epiretinal membranes in patients with diabetic retinopathy, leading to tractional retinal detachment.4 Indeed, the development of inhibitors that antagonize PDGF signaling in pathologic retinal neovascularization a hallmark of proliferative diabetic retinopathy remains an active area of ophthalmic drug development.5 Rajesh C. Rao, M.D.
Washington University School of Medicine St. Louis, MO raor@vision.wustl.edu

Brian J. Dlouhy, M.D.

University of Iowa Hospitals and Clinics Iowa City, IA No potential conflict of interest relevant to this letter was reported.
1. Praidou A, Papakonstantinou E, Androudi S, Georgiadis N,

N Engl J Med 2012;366:1227-39.

with retinitis pigmentosa: implications for pathophysiology and possible treatment. Br J Ophthalmol 2001;85:366-70. 3. Hagins WA, Ross PD, Tate RL, Yoshikami S. Transduction heats in retinal rods: tests of the role of cGMP by pyroelectric calorimetry. Proc Natl Acad Sci U S A 1989;86:1224-8. 4. Wong A, Merritt S, Butt AN, Williams A, Swaminathan R. Effect of hypoxia on circulating levels of retina-specific messenger RNA in type 2 diabetes mellitus. Ann N Y Acad Sci 2008; 1137:243-52. 5. Mason RH, Klire CA, Groves DC, et al. Visual improvement following continuous positive airway pressure therapy in diabetic subjects with clinically significant macular oedema and obstructive sleep apnoea: proof of principle study. Respiration 2011 December 20 (Epub ahead of print).

Karakiulakis G, Dimitrakos S. Vitreous and serum levels of vascular endothelial growth factor and platelet-derived growth factor and their correlation in patients with non-proliferative diabetic retinopathy and clinically significant macula oedema. Acta Ophthalmol 2011;89:248-54. 2. Praidou A, Klangas I, Papakonstantinou E, et al. Vitreous and serum levels of platelet-derived growth factor and their correlation in patients with proliferative diabetic retinopathy. Curr Eye Res 2009;34:152-61. 3. Vinores SA, Seo MS, Okamoto N, et al. Experimental models of growth factor-mediated angiogenesis and blood-retinal barrier breakdown. Gen Pharmacol 2000;35:233-9. 4. Mori K, Gehlbach P, Ando A, et al. Retina-specific expression of PDGF-B versus PDGF-A: vascular versus nonvascular proliferative retinopathy. Invest Ophthalmol Vis Sci 2002;43:2001-6. 5. Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 2006;168:2036-53.
DOI: 10.1056/NEJMc1205011

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